Stereoselective preparation of a cyclopentane-based NK1 receptor antagonist bearing an unsymmetrically substituted sec-sec ether |
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Authors: | Kuethe Jeffrey T Marcoux Jean-Francois Wong Audrey Wu Jimmy Hillier Michael C Dormer Peter G Davies Ian W Hughes David L |
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Affiliation: | Department of Process Research, Merck and Company, Incorporated, P.O. Box 2000, Rahway, New Jersey 07065, USA. Jeffrey_Kuethe@Merck.com |
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Abstract: | A highly efficient synthesis of the potent and selective NK-1 receptor antagonist 1 is described. The key transformation involved the etherification reaction between cyclopentanol 12 and chiral imidate 30 which was catalyzed by HBF4 to initially give ether 14 as a 17:1 mixture of diastereomers and in 75% combined yield. The diastereoselectivity was upgraded to 109:1 by crystallization of the triethylamine solvate 44 which was isolated in 54% yield from 12. Mechanistic studies confirmed that the etherification reaction proceeds through an unprecedented S(N)2 reaction pathway under typical S(N)1 reaction conditions. |
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